Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge Study

Chronic Kidney Disease Clinical Trial

— CONTINUITY  

Official title:

An Open-Label, Randomised, Phase 4 Study of Continuing Sodium Zirconium Cyclosilicate (SZC) After Discharge in Participants With Chronic Kidney Disease Treated for Hyperkalaemia

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05347693
• Other study ID #: D9480C00023
• Secondary ID: 2021-003527-14
• Status: Recruiting
• Phase: Phase 4
• Start date: March 24, 2022
• Est. completion date: December 25, 2024

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is an open-label, randomised study in participants with chronic kidney disease (CKD) treated for hyperkalaemia (HK) whilst in hospital. The study will compare SZC to standard of care (SoC) with the goal of determining:

• If continued use of SZC maintains normokalaemia (NK) better than SoC after participant discharge from the hospital.

• If continued use of SZC after discharge will reduce HK related healthcare resource utilisation compared to SoC.

Description:

This is a Phase 4, randomised, controlled, open-label, parallel-group, multicentre study in participants with CKD treated for HK whilst in hospital.

• Participants from 30 to 50 sites in 4 to 7 countries will be screened for enrolment. In total, up to a maximum of 163 participants will be enrolled, resulting in approximately 130 participants discharged and randomised and 104 evaluable participants (52 per arm).

• The study plans to enrol approximately equal numbers of participants with mild HK (K+ between > 5.0 and ≤ 5.5 mmol/L) and with moderate/severe HK (K+ between > 5.5 and ≤ 6.5 mmol/L), with a minimum of 30% of the enrolled participants in either group.

• During the in-hospital phase, participants will be treated with SZC as per local label, starting at baseline and based on local K+ measurement obtained within 24 hours of treatment initiation:).

• Participants with HK (K+ between > 5.0 and ≤ 6.5 mmol/L):

1. stop current K-binder if any

2. start SZC correction dose (note: participants currently on SZC should continue SZC correction dose, up to 72 hours).

• Participants currently receiving any treatment for the current episode of HK and are already NK at baseline (K+ ≤ 5.0 mmol/L): 1) stop any current K-binder, 2) start SZC maintenance dose (note: participants currently on SZC maintenance dose should continue SZC maintenance dose).

• All treatment decisions, including modification of the ongoing therapy for HK must be based on the investigator's medical judgement of the participant's best interest.

• At discharge, NK participants who have been treated with SZC for between 1 and 21 days whilst in hospital and are started on SZC maintenance dose will be randomised in a 1:1 ratio to one of the following arms:

• Arm A: Participants discharged with SZC, as per local label, to manage HK until the end of the outpatient phase

• Arm B: Participants discharged with SoC, as per local practice, to manage HK until the end of study. Note: Participants intended to be discharged with a K+ binder (as per the site routine medical practice) will not be randomised and will be discontinued from the study. Still, participants randomised into Arm B may have a K-binder prescribed at Day 7 post-discharge, (or after Day 7 post-discharge), to treat confirmed HK or in case there is an increase in K+ level since discharge that, in the investigator's opinion, requires therapy.

• The total duration of the study for each participant will be up to approximately 6 months.

• Study visit schedule is as follows:

In-hospital phase: - The screening visit will occur while the participant is at the hospital (up to 21 days before discharge; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants) in order to check eligibility criteria

• Inpatient phase: o The baseline visit (can occur the same day as the screening visit) where treatment with SZC will be initiated

o The discharge visit, 1 to 20 days after baseline; medical monitor's approval may be sought for allowing longer duration hospital stays for specific participants). Randomisation will occur at day of discharge.

• Outpatient phase: - Visits will occur at 7, 30, 60, 90, 120, 150, and 180 (EOT, End of Trial) days after randomisation. Only visits at 7, 90 and 180 days after randomisation will be on-site visits, the remaining being telephone visits. If dose titration occurs at any time during the outpatient phase, unscheduled dispensation visits will be performed.

Follow-up phase: - A follow-up on-site visit (end of study visit) will occur approximately 7 days after EOT. • Data will be collected at on-site visits, via telephone visits and medical chart reviews.

• An adjudication committee will be involved in the study.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 130
• Est. completion date: December 25, 2024
• Est. primary completion date: December 25, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 130 Years

Eligibility

Inclusion Criteria:

• Must be 18 years of age or older, at the time of signing the informed consent

• Admitted to hospital (inpatient care; directly or from ED)

• With:

1. Diagnosed CKD (any stage) or

2. eGFR < 90 ml/min/1.73 m2 at, or within 3 months of, study screening, based on the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (Levey et al, 2009).

Note: Race/ethnicity should not be included in CKD-EPI equation calculation.

• Local laboratory K+ measurement within 24 hours of baseline visit (visit 2), where result is either:

• Hyperkalaemic as defined by site's local practice and K+ = 6.5 mmol/L.

• Or, normokalaemic: K+ between = 3.5 and = 5.0 mmol/L, where patient started and is receiving treatment for this episode of HK

• Male or female

• Capable and willing of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

• Hospitalisation for an acute cardiovascular event within 12 weeks prior to screening

• Unable to take oral SZC drug mix

• With a life expectancy of less than 6 months

• Any medical condition that, in the opinion of the investigator makes the participant not suitable for inclusion

• QT interval corrected by the Fridericia method (QTcF) > 550 msec

• History of QT prolongation associated with other medications that required discontinuation of that medication

• Congenital long QT syndrome

• Clinically significant arrythmias as judged by the investigator

• Ongoing treatment with SZC or patiromer before current ED visit/hospital admission (ongoing treatment with other K-binders before current ED visit/hospital admission is allowed).

Note: Initiation of any SZC or patiromer during the current ED visit/hospitalisation preceding enrolment is allowed.

• Chronic haemodialysis or peritoneal dialysis or the recipient of or scheduled date for a kidney transplant. Note: Emergency/unscheduled haemodialysis to treat HK during the current ED visit/hospitalisation preceding enrolment is allowed.

• Participation in another clinical study with an investigational medicinal product (IMP) administered during the month before screening.

• Known hypersensitivity to SZC or any of the excipients of the product

• Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)

• Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements

• Previous randomisation in the present study

• For women only: Women of child-bearing potential (WOCBP; ie, those who are not chemically or surgically sterilised or who are not post-menopausal) who are not willing to use one of the methods of contraception described hereafter, or who are not stable on the contraception method for the last one month, from the time of signing the informed consent throughout the study and 7 days after the last dose: (a) Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: oral, intravaginal, transdermal (b) Progestogen-only hormonal contraception associated with inhibition of ovulation: oral, injectable, implantable (c) Intrauterine device (d) Intrauterine hormone-releasing system (e) Bilateral tubal occlusion (f) Vasectomised partner (vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the WOCBP participant and that the vasectomised partner has received medical assessment of the surgical success (g) Sexual abstinence: it is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant.

• For WOCBP only: Women who have a positive pregnancy test at screening OR women who are breastfeeding.

Related Conditions & MeSH terms

• Chronic Kidney Disease
• Hyperkalaemia
• Hyperkalemia
• Kidney Diseases
• Renal Insufficiency, Chronic

Intervention

Drug:
• Sodium Zirconium Cyclosilicate (SZC)
White to grey crystalline powder for oral suspension in 5 g sachets. Each sachet will be labeled in accordance with Good Manufacturing Practice Annex 13 and per country regulatory requirement. Label text will be translated into local language.
• Local standard of care
Local SoC in the country to be used as per local label

Locations

Country	Name	City	State
Belgium	Research Site	Belgium
Belgium	Research Site	Bonheiden
Belgium	Research Site	Dendermonde
Belgium	Research Site	Leuven
Belgium	Research Site	Lodelinsart
France	Research Site	Annonay
France	Research Site	Ars-Laquenexy
France	Research Site	La Tronche
France	Research Site	Nice
France	Research Site	Saint-priest En Jarez
Germany	Research Site	Kaiserslautern
Italy	Research Site	Acireale
Italy	Research Site	Bari
Italy	Research Site	Foggia
Italy	Research Site	Parma
Italy	Research Site	Pavia
Italy	Research Site	Pavia
Italy	Research Site	Roma
Netherlands	Research Site	Amsterdam
Netherlands	Research Site	Eindhoven
Netherlands	Research Site	Groningen
Netherlands	Research Site	Rotterdam
Spain	Research Site	Alcalá De Henares
Spain	Research Site	Algeciras
Spain	Research Site	Alicante
Spain	Research Site	Almería
Spain	Research Site	Badajoz
Spain	Research Site	Barcelona
Spain	Research Site	Burgos
Spain	Research Site	Getafe
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Madrid
Spain	Research Site	Palma de Mallorca
Spain	Research Site	Salamanca
Spain	Research Site	San Sebastián de los Reyes
Spain	Research Site	Santiago de Compostela
Spain	Research Site	Sevilla
Spain	Research Site	Talavera de la Reina
Spain	Research Site	Zamora
United Kingdom	Research Site	Cardiff
United Kingdom	Research Site	Doncaster
United Kingdom	Research Site	Edinburgh
United Kingdom	Research Site	Hull
United Kingdom	Research Site	Leicester
United Kingdom	Research Site	London
United Kingdom	Research Site	Salford
United Kingdom	Research Site	Stevenage
United Kingdom	Research Site	York

Sponsors (1)

Lead Sponsor	Collaborator
AstraZeneca

Countries where clinical trial is conducted

Belgium,  France,  Germany,  Italy,  Netherlands,  Spain,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Adverse Events (AE)	Assessments related to AEs cover: Occurrence/frequency, Relationship to SZC as assessed by investigator, Intensity, Seriousness, Death, AEs leading to discontinuation of SZC.	From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
Other	Weight in kilograms	Weight will be measured using the same scale and in the same state of dress as part of vital signs	From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
Other	Height in centimeters	Height will be measured as part of vital signs.	Height will be measured at screening visit
Other	Blood pressure (BP) in mmHg	Blood pressure should be measured with a completely automated device in triplicate with at least 1-minute intervals between measurements after being comfortably at rest in a seated position with the back and feet supported quietly for at least 5 minutes. Manual techniques will be used only if an automated device is not available. The same device should preferably be used for the participant during the course of the study and in the same arm.	From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
Other	Pulse rate in beats/min	Pulse rate should be measured with a completely automated device in triplicate with at least 1-minute intervals between measurements after being comfortably at rest in a seated position with the back and feet supported quietly for at least 5 minutes. Manual techniques will be used only if an automated device is not available. The same device should preferably be used for the participant during the course of the study and in the same arm.	From time of signature of the ICF, throughout the treatment period and including the follow-up period, 201 days maximum
Other	Clinical safety laboratory tests	Serum electrolytes values(mmol/L), serum BUN(mmol/L), urinalysis and others	From time of signature of the ICF, throughout the treatment period and the follow-up period, 201 days maximum
Other	Electrocardiograms (ECG)	An ECG will be performed throughout study participation and according to clinical judgment in connection with severe hypokalaemia (K+ < 3.0 mmol/L), severe HK (K+ > 6.0 mmol/L), or any symptoms or clinical events suggesting cardiac arrhythmia.	From time of signature of the ICF, throughout the treatment period and the follow-up period, 201 days maximum
Other	Time to first occurrence of any component of hospital admission or ED visit, both with HK as a contributing factor, or all-cause death	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of the composite outcome of hospital admissions or ED visits with HK as a contributing factor or all-cause death	Up to 180 days post-discharge
Other	Time to first occurrence of either hospital admission with HK as a contributing factor or allcause death	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of hospital admissions with HK as a contributing factor or all-cause death	Up to 180 days post-discharge
Other	Time to first occurrence of either ED visit with HK as a contributing factor or all-cause death	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of ED visits with HK as a contributing factor or all-cause death	Up to 180 days post-discharge
Other	Time to first occurrence of any component of all-cause hospitalisations, ED visits, use of rescue therapy for HK or all-cause death in each arm	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of the composite outcome of all-cause hospitalisations, ED visits, all cause death, or use of rescue therapy for HK	Up to 180 days post-discharge
Other	K+ level	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, on mean K+ levels	Up to 180 days post-discharge
Other	Number of hospital admissions with HK as a contributing factor	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the number of hospital admissions with HK as a contributing factor	Up to 180 days post-discharge
Other	Time to first occurrence of K-binder use in each arm	To evaluate the effect of continuing SZC as part of discharge medications, compared to SoC in reducing the incidence of K-binder use	Up to 180 days post-discharge
Other	Frequency of the use of K-binder to treat HK in each arm	To evaluate the effect of continuing SZC as part of discharge medications, compared to SoC in reducing the frequency and duration of K-binder use	Up to 180 days post-discharge
Other	Time to first occurrence of rescue therapy use in each arm	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of rescue therapy for HK use	up to 180 days post-discharge
Other	Time to first occurrence of all-cause hospitalisations, ED visits, or outpatient visits in each arm	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of the composite outcome of all-cause hospitalisations, ED visits, or outpatient visits	up to 180 days post-discharge
Other	Rate of change in (slope) eGFR (estimated glomerular filtration rate) from inpatient phase	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in the change in eGFR	90 and 180 days post-discharge
Other	Time to first occurrence of dialysis initiation in each arm	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in the incidence of dialysis initiation	up to 180 days post-discharge
Other	Time to first occurrence of ICU (intensive care unit) admissions in each arm	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of ICU admissions	up to 180 days post-discharge
Other	Frequency (%) of participants on RAASi (renin-angiotensin-aldosterone system inhibitor) at discharge who remained on / increased / decreased / initiated RAASi	This exploratory endpoint will descriptively summarise the use of RAASi in each treatment arm	90 and 180 days post-discharge
Primary	Occurrence (yes/no) of normokalaemia (NK) (potassium [K+] between 3.5 and 5.0 mmol/L, inclusive)	To evaluate the efficacy of continuing SZC as part of the discharge medications, compared to SoC, in maintaining NK	Up to 180 days post-discharge
Secondary	Time to first occurrence of all-cause hospital admissions or ED visits with HK as a contributing factor, all-cause death, or use of rescue therapy for HK	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of the composite outcome of all-cause hospital admissions or ED visits with HK as a contributing factor, or all-cause death, or use of rescue therapy for HK	Up to 180 days post-discharge
Secondary	Time to first occurrence of all-cause hospital admission or ED visit, with HK as a contributing factor	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of hospital admissions or ED visit with HK as a contributing factor	Up to 180 days post-discharge
Secondary	Number of all-cause hospital admission or ED visits, with HK as a contributing factor	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the number of all-cause hospital admissions or ED visits with HK as a contributing factor	Up to 180 days post-discharge
Secondary	Time to first occurrence of hospital admission or ED visit with HK as a contributing factor between the SZC and SoC arms.	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the incidence of hospital admissions or ED visits with HK as a contributing factor.	Up to 180 days post-discharge
Secondary	Incidence rate of hospital admission or ED visit with HK as a contributing factor between the SZC and SoC arms.	To evaluate the effect of continuing SZC as part of the discharge medications, compared to SoC, in reducing the number of hospital admissions or ED visits with HK as a contributing factor.	Up to 180 days post-discharge
Secondary	Time to first occurrence of RAASi down-titration (or discontinuation)	To evaluate the effect of continuing SZC as part of the discharge medications compared to SoC on reducing the risk of RAASi down-titration (or discontinuation)	Up to 180 days post-discharge